Personalized elective neck irradiation guided by sentinel lymph node biopsy in patients with squamous cell carcinoma of the oropharynx, larynx or hypopharynx with a clinically negative neck: (chemo)radiotherapy to the PRIMary tumor Only. The PRIMO study.

Squamous cell carcinoma of the upper aerodigestive tract comes with a
substantial risk for cervical lymph node metastases. Elective neck irradiation
is performed in patients receiving (chemo)radiotherapy aiming to eradicate
nodal metastases that are under the diagnostic detection level. Most toxicity
and permanent long-term radiation side effects are caused by elective neck
irradiation. In particular xerostomia and dysphagia are notoriously known to
negatively and permanently affect quality of life. Sentinel lymph node biopsy
has emerged as a staging procedure that can reliably detect microscopic
metastases by histopathological examination of sentinel lymph nodes and the
pathologic status of the sentinel lymph node accurately reflects the status of
the remaining nodal basin. A recent meta-analysis demonstrated an excellent
diagnostic test accuracy of sentinel lymph node biopsy in patients with cancer
of the oropharynx, larynx and hypopharynx (sensitivity 0.93 and negative
predictive value 0.97). It is conceivable that personalized elective neck
irradiation can be performed guided by the results of sentinel lymph node
biopsy. With this approach it is expected that elective neck irradiation can be
omitted in the majority of patients with a clinically negative neck because
occult nodal metastases are present approximately in 3 out of 10. This will
enable better sparing of normal tissues from radiation and consequentially
result in less permanent long-term radiation side effects with better quality
of life after treatment.

To compare safety and efficacy of treatment with sentinel lymph node biopsy
guided elective neck irradiation versus standard elective neck irradiation in
patients receiving definitive (chemo)radiotherapy for squamous cell carcinoma
of the oropharynx, larynx or hypopharynx.

This is a multicenter, randomized controlled trial. In total 242 patients will
be randomized in ratio 1:1 to the control arm with standard bilateral elective
neck irradiation or to the interventional arm with sentinel lymph node biopsy
guided personalized elective neck irradiation. During a 2 year follow-up, data
on toxicity, quality of life and oncologic outcomes will be collected.
If this trial demonstrates that the interventional treatment is non-inferior to
the standard treatment in terms of regional recurrence and is superior in terms
of xerostomia-related quality of life, this will become the new standard of
care.

Patients randomized to the intervention arm will undergo sentinel lymph node
biopsy. Based on the histopathologic status of the sentinel lymph node(s),
patients will receive no elective neck irradiation (if all sentinel lymph nodes
are negative), unilateral only (if a sentinel lymph node is positive at one
side of the neck) or bilateral (if sentinel lymph nodes are positive at both
sides of the neck). For patients randomized to the control arm sentinel lymph
node biopsy will not be performed and all will receive standard bilateral
elective neck irradiation.

Burden associated with participation | Patients randomized to the intervention
arm will undergo sentinel lymph node biopsy (flexible endoscopic tracer
injection under topical anesthesia in the outpatient clinic, SPECT/CT-scan and
surgical removal of identified sentinel lymph nodes under general anesthesia).
These procedures will not be performed in patients in the control arm. For
patients randomized to the intervention arm there is a potential increased risk
for regional recurrence because elective neck irradiation is omitted based on
the histopathologic status of the sentinel lymph node(s). However this risk is
expected to be very small (3.1% versus 2.0% in the control arm). Because
regional recurrences can be cured in 70-90% of the patients with salvage neck
dissection, the effect on overall survival is expected to be negligible.
Independent of randomization, participants will undergo non-invasive procedures
to objectify radiation sequelae and will be asked to complete quality of life
questionnaires.
Benefit associated with participation | With sentinel lymph node biopsy, it is
expected that futile elective neck irradiation can be omitted to one or both
sides of the neck in 9 out of 10 patients. This will enable better sparing of
normal tissues from radiation and it is expected that this will result in a
major decrease of permanent long-term radiation side effects (such as
xerostomia and dysphagia) with better quality of life after treatment compared
to standard elective neck irradiation.